In substance abusers, the propensity to attribute incentive salience to cues and allow these cues to capture attention is thought to be causally related to response inhibition deficits, including cognitive and motor impulsivity, Aim 1 of Project 4 will characterize the attentional capacities of Sign Trackers (STs) and demonstrate that compared to Goal Trackers (GTs), STs exhibit a limited capacity to sustain attention and a propensity for impulsive responses. STs' attentional performance is hypothesized to be due to impaired top- down control mechanisms, including ineffective modification of perfonnance in response to errors and reward loss. Aim 2 concerns the prefrontal cholinergic mechanisms that mediate the relatively poor attentional performance of STs. Preliminary evidence is consistent with the hypothesis that prefrontal giutamatergic-cholinergic interactions are differently regulated in STs and contribute to their comparatively lower attentional performance. Aim 3 will demonstrate that blocking a specific node in this circuit, presynaptic alpha4beta2* nAChRs expressed by thalamic afferents, causes ST-like performance impairments in GTs. Conversely, stimulation of alpha4beta2* nAChRs improves the attentional performance of STs. Aim 4 will extend this research to the impact of cues that were associated with cocaine self- administration and are capable of producing addiction-like behavior and relapse. The presence of such a drug cue is expected to abolish the ability of STs to sustain cognitive performance, in part as a result of cue- evoked, excessively large and lasting prefrontal cholinergic transients that interfere with the detection of task signals. These drug cue-evoked, excessive release events also contribute to the relative inability of STs to re-engage in cognitive task perfonnance. Collectively, this research is guided by the hypothesis that lower levels of cognitive control combined with attentional bias toward drug-related cues are key cognitive traits in individuals vulnerable for addiction. The neurochemical mechanisms underiying the detrimental efTicacy of the drug cue in STs form the basis of therapeutic interventions designed to limit dmg-cue evoked behavior and foster re-engagement in cognitive task performance (Aim 4). RELEV/VNCE (See Instructions): Addiction is a major public health problem in the United States. The goal of this Project is to use a preclinical model to delineate the psychological and neurobiological basis of individual differences in vulnerabilty to develop addiction-like behavior, as this will help identify risk factors that will aid in the development of targeting interventions and treatments.